POS0859 VENOUS AND ARTERIAL THROMBOEMBOLIC RISK OF JAK INHIBITORS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: F. Campanaro, A. Batticciotto, A. Zaffaroni, M. P. Donadini, A. Squizzato, A. Cappelli
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> JAK inhibitors (JAKi) are a new class of drugs developed for the treatment of different immune-mediated inflammatory diseases (IMIDs). Thrombotic events have been reported in some long-term extension studies as adverse effects. As a consequence, in 2017 the Food and Drug Administration (FDA) inserted a black box warning in the Summary of Product Characteristics (SPC) for Baricitinib, stating that it should be used with caution in patients at increased risk of thrombosis [1]. A similar warning was issued by the European Medicines Agency (EMA) in 2019 for Tofacitinib 10 mg [2]. <h3>Objectives</h3> To perform a systematic review of randomized controlled trials (RCTs) with the aim to estimate the risk of venous and arterial thromboembolic (TE) events in patients with IMIDs treated with JAKi. <h3>Methods</h3> RCTs on the efficacy and safety of JAKi in IMIDs patients were identified by electronic search of the MEDLINE and EMBASE database until October 2021. Risk of bias was assessed according to Cochrane criteria. All JAKi and all IMIDs were included in the main analysis. Venous and arterial TE events (deep vein thrombosis, pulmonary embolism, unusual site thrombosis, superficial venous thrombosis, stroke, transient ischemic attack, coronary ischaemic events and peripheral artery ischaemia) and major adverse cardiovascular events (MACE) were extracted from the reported safety analysis of the different RCTs. Studies which did not report any information on the cardiovascular safety profile in the paper or supplementary materials were excluded. Differences in thrombotic outcomes among groups were expressed as pooled odds ratio (OR) and corresponding 95% confidence interval (CI), using both a fixed-effects and a random-effects model. Statistical heterogeneity was evaluated using the I² statistic. <h3>Results</h3> One phase I, 21 phase II, 3 phase II-III and 36 phase III RCTs on Rheumatoid Arthritis (32.8%), Atopic Dermatitis (22.9%), Psoriasis (11.5%), Inflammatory Bowel Disease (11.5%), Psoriatic Arthritis (9.8%), Ankylosing Spondylitis (6.6%) and Lupus Erytheratosus (4.9%) were included, for a total of 19443 patients in the JAKi group (Abrocitinib, Baricitinib, Brepocitinib Deucravacitinib, Filgotinib, Ivarmacitinib, Peficitinib, Tofacitinib and Upadacitinib) and 9073 in the placebo group. Thirty-one (unweighted rate 0.16%) TE events were reported in the JAKi group and 20 (unweighted rate 0.22%) in the control group in an unweighted mean follow-up of 16.8 weeks. IMIDs patients treated with JAKi had not an increased TE risk compared to IMIDs patients treated with placebo (OR 0.69 [95% CI, 0.44–1.10, I<sup>2</sup> 0%] at fixed-effect model) (Figure 1). No clinically relevant results were seen among different IMIDs and drugs. The ORs of venous and arterial TE events were respectively 0.61 (95% CI, 0.32–1.15, I<sup>2</sup> 0%) and 0.78 (95% CI, 0.41–1.48, I<sup>2</sup> 0%) at fixed-effect model. The incidence of MACE was similar among the groups (OR 0.82 [95% CI, 0.48–1.40, I<sup>2</sup> 0%] at fixed-effect model). <h3>Conclusion</h3> Despite our study has some limits like the short duration of the RCTs, the different inclusion criterias, permitted concomitant therapies, mean age and mean disease activity, we did not find any evidence that JAKi increase the risk of venous and arterial TE events and MACE. The performed sub-analysis did not find any correlation between the use of any JAKi and TE events in any considered IMID, even if the meta-analysis is likely underpowered (i.e. β error) to highlight statistically significant differences of the incidence of TE events between different diseases and different JAKi. JAKi do not increase TE risk compared to placebo in IMIDs patients enrolled in phase I/II/III RCTs. <h3>References</h3> [1]Olumiant (baricitinib) prescribing information. Indianapolis (IN): Lilly; 2018. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207924s000lbl.pdf [2]EMA confirms Xeljanz to be used with caution in patients at high risk of blood clots. URL: https://www.ema.europa.eu/en/documents/press-release/ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots_en.pdf <h3>Acknowledgements</h3> Andrea Zaffaroni took part in this study as participant to the scientific research training project for medical students of the University of Insubria, Italy, named 'Recruiting and training physicians-scientists to empower translational research. A multilevel transdisciplinary approach focused on methodology, ethics and integrity in biomedical research - 2018-2023' and funded by Fondazione Cariplo, Italy. <h3>Disclosure of Interests</h3> None Declared.